by Buck Institute

How Does Obesity Increase the Risk for Severe Covid-19 (and other infections, too)?

Spoiler alert: it’s inflammation

As Covid-19 became part of our lives in late 2019 and early 2020, a fascinating and disturbing aspect that quickly became apparent was the range of effects that it had on those infected, from no symptoms at all to death. With time, a host of risk factors for severe disease and death emerged, including age, male gender, high blood pressure, type 2 diabetes, and obesity.

Obesity is a recurring theme. The highest rates of COVID-19 deaths are seen in high-income countries, which have the highest life expectancy and wealth, but also a high incidence of obesity. Age and obesity are also risk factors for “long COVID,” defined as signs or symptoms of infection lasting longer than two weeks. Obesity also increases risk for other infectious diseases, including influenza and the previous SARS outbreaks (SARS-CoV-1 and MERS-CoV).

What is it about having excess body fat that makes respiratory and other infections worse?

To answer that question, we asked Buck Institute associate professor David Furman, PhD, to summarize what he has discovered so far, how it applies to infections and many chronic diseases in general, and what he is working on to remedy the problem.

One point that Furman emphasizes is that it doesn’t make sense to draw a sharp line between the various risk factors for a more severe infection, because all of the risk factors are closely connected through a common thread: inflammation.

Inflammation lacks a precise definition

For perspective, it helps to understand what inflammation actually is. Furman admits that overall, the term is ill-defined (his team is currently working on publishing a paper outlining a precise definition), but he describes it in general as the body’s response to damage or stress. “It is an irregularity that the body senses, which could be infection or other environmental cues,” he says.

On the molecular and cellular level, a stressor (such as a virus) contains molecules on its surface that bind to receptor molecules on the surface of immune cells. This sets off a whole cascade of reactions, triggering the expression of genes and the recruitment of an arsenal of immune cells to the site of the activity. The classic signs of this acute inflammatory response are redness and swelling.

The problem occurs when the very useful and necessary acute inflammatory response to a stressor turns into chronic, systemic inflammation that does nothing helpful for the body. Furman emphasizes that this is a different type of inflammation originated from environmental triggers other than infections.

This chronic, low-grade systemic inflammation, as opposed to the transient and acute inflammatory response, has been called “metaflammation” (for “metabolic inflammation”). Obesity is characterized by metaflammation, and is at the root of the increased risk of type 2 diabetes, cardiovascular disease, cancer, nonalcoholic fatty liver disease and immune system dysfunction.

With obesity, metaflammation means that the excess body fat is inflamed and constantly churning out chemicals that interfere with the normal signaling of the immune system.

With obesity, metaflammation means that the excess body fat is inflamed and constantly churning out chemicals that interfere with the normal signaling of the immune system. 

This interference causes a blunted immune response that allows the virus to multiply rapidly.  Major damage is caused by the virus and by the immune system, which then overreacts, causing an over-production of immune molecules (a “cytokine storm”) and the increased blood clotting (hypercoagulation), which are key factors in severe COVID-19 infection.

“If two patients have the same infection, one with chronic metaflammation will be more likely to experience complications,” says Furman.

The bottom line, he says, is that prevention measures should not only include the established actions such vaccination, social distancing, and masking, but also dietary and lifestyle interventions that can improve body composition and prevent or reverse metaflammation.

Getting to interventions

“The most important message is that there are triggers that we can all prevent, namely processed foods, high sugar diets, etc.,” he says. “Everybody knows this on some level, we should eat more nutritious foods and exercise more.” The question is what to do about the fact that many people do not follow this advice.

Furman has a number of ideas. Central to the research at the Furman lab is analyzing enormous amounts of data to reveal how the immune system affects aging and related chronic diseases.

“One-size-fits-all treatment means getting rid of the trigger, but is there fine-tuning we could do to prevent inflammation from expanding and continuing over the lifespan?” he wonders. “If we could take a profile, and then give interventions that will put someone in a healthier state, by bumping up proteins present in low quantities, and suppressing expression of proteins that are leading the inflammatory process and giving nasty outcomes, we have the way to precision medicine.”

Beyond interventions to treat or prevent progression to the diseases triggered by inflammation, Furman has also embarked on an intriguing project aimed at assisting with the problem that most people know what they should be doing but are unable or unwilling to make changes.

“Classical psychiatry has failed us by and large,” he says, and by using various ways of trying to understand and change people’s behavior, he is developing scientifically based individualized “profiles of change,” using computational psychiatry, in which he applies computational modeling and theoretical approaches to behavior change.

“We don’t have a final answer yet, but there is hope as we’re actively investigating this,” he says.

Furman was part of a team that comprehensively reviewed studies to date that cover obesity and COVID-19 in an article published in the March 26 issue of Nutrients. Furman directs the Stanford 1000 Immunomes Project at Stanford University School of Medicine and is Chief of the Buck AI Platform at the Buck Institute for Research on Aging.


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